tbuckley/cabot-search huggingface dataset:
The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Mandy Lawson, Natalie Cureton, Susana Ros, Azadeh Cheraghchi-Bashi, Jelena Urosevic, Sophie D'Arcy, Oona Delpuech, Michelle DuPont, David I. Fisher, Eric T. Gangl, Hilary Lewis, Dawn Trueman, Neha Wali, Stuart C. Williamson, Jennifer Moss, Elodie Montaudon, Heloise Derrien, Elisabetta Marangoni, Ricardo J. Miragaia, Sladjana Gagrica, Pablo Morentin-Gutierrez, Thomas A. Moss, Gareth Maglennon, Daniel Sutton, Radoslaw Polanski, Alan Rosen, Jonathan Cairns, Pei Zhang, Mònica Sánchez-Guixé, Violeta Serra, Susan E. Critchlow, James S. Scott, Justin P.O. Lindemann, Simon T. Barry, Teresa Klinowska, Christopher J. Morrow, Larissa S. Carnevalli
Journal: Cancer Research (2023)

Abstract Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor–positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER–co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi. Significance: Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.
Advanced Age in Humans and Mouse Models of Glioblastoma Show Decreased Survival from Extratumoral Influence
Authors: Margaret Johnson, April Bell, Kristen L. Lauing, Erik Ladomersky, Lijie Zhai, Manon Penco-Campillo, Yajas Shah, Elizabeth Mauer, Joanne Xiu, Theodore Nicolaides, Michael Drumm, Kathleen McCortney, Olivier Elemento, Miri Kim, Prashant Bommi, Justin T. Low, Ruba Memon, Jennifer Wu, Junfei Zhao, Xinlei Mi, Michael J. Glantz, Soma Sengupta, Brandyn Castro, Bakhtiar Yamini, Craig Horbinski, Darren J. Baker, Theresa L. Walunas, Gary E. Schiltz, Rimas V. Lukas, Derek A. Wainwright
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan. Experimental Design: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. Results: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. Conclusions: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
Prospects and challenges of in vivo hematopoietic stem cell genome editing for hemoglobinopathies
Authors: André Lieber, Hans-Peter Kiem
Journal: Molecular Therapy (2023)

There has been tremendous progress in the field of hematopoietic stem cell (HSC) gene therapy, especially for hemoglobinopathies. Recently, bluebird bio received FDA approval to use their lentiviral vector (delivering a functional beta globin gene) for the treatment of transfusion-dependent thalassemia, and approval to use this vector for the treatment of sickle cell disease (SCD) is expected in the near future. Similar promising results have been observed with CRISPR-mediated editing, and Vertex/CRISPR are also nearing approval for their approach to reactivate fetal hemoglobin. However, what these approaches have in common is that they are all carried out ex vivo ("outside the body") and require sophisticated infrastructure that would not generally be available in low- or middle-income countries or, for that matter, in resource-limited regions in high-income countries. In addition, these ex vivo approaches are very costly, with approved treatments expected to cost $2 to $3 million dollars, and they will not be a viable option for the millions of people affected in less-affluent countries. Thus, while promising and important, current ex vivo gene therapies are not a realistic option for most patients and would likely provide curative therapy for fewer than 1% of patients with SCD worldwide. If, however, one could deliver the gene therapy or editing tools and target HSC directly in vivo, the process would possibly be far less complicated, less expensive, and more accessible to those in need, wherever they may reside (Figure 1).
Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
Authors: Jonathan Paolino, Boris Dimitrov, Beth Apsel Winger, Angelica Sandoval-Perez, Amith Vikram Rangarajan, Nicole Ocasio-Martinez, Harrison K. Tsai, Yuting Li, Amanda L. Robichaud, Delan Khalid, Charlie Hatton, Riaz Gillani, Petri Polonen, Anthony Dilig, Giacomo Gotti, Julia Kavanagh, Asmani A. Adhav, Sean Gow, Jonathan Tsai, Yen Der Li, Benjamin L. Ebert, Eliezer M. Van Allen, Jacob Bledsoe, Annette S. Kim, Sarah K. Tasian, Stacy L. Cooper, Todd M. Cooper, Nobuko Hijiya, Maria Luisa Sulis, Neerav N. Shukla, Jeffrey A. Magee, Charles G. Mullighan, Michael J. Burke, Marlise R. Luskin, Brenton G. Mar, Matthew P. Jacobson, Marian H. Harris, Kimberly Stegmaier, Andrew E. Place, Yana Pikman
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. Experimental Design: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. Results: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. Conclusions: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.
Entinostat Enhances the Efficacy of Chemotherapy in Small Cell Lung Cancer Through S-phase Arrest and Decreased Base Excision Repair
Authors: Anna Solta, Kristiina Boettiger, Ildikó Kovács, Christian Lang, Zsolt Megyesfalvi, Franziska Ferk, Miroslav Mišík, Konrad Hoetzenecker, Clemens Aigner, Christian R. Kowol, Siegfried Knasmueller, Michael Grusch, Beáta Szeitz, Melinda Rezeli, Balazs Dome, Karin Schelch
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Acquired chemoresistance is a frequent event in small cell lung cancer (SCLC), one of the deadliest human malignancies. Histone deacetylase inhibitors (HDACi) have been shown to synergize with different chemotherapeutic agents including cisplatin. Accordingly, we aimed to investigate the dual targeting of HDAC inhibition and chemotherapy in SCLC. Experimental Design: The efficacy of HDACi and chemotherapy in SCLC was investigated both in vitro and in vivo. Synergistic drug interactions were calculated based on the HSA model (Combenefit software). Results from the proteomic analysis were confirmed via ICP-MS, cell-cycle analysis, and comet assays. Results: Single entinostat- or chemotherapy significantly reduced cell viability in human neuroendocrine SCLC cells. The combination of entinostat with either cisplatin, carboplatin, irinotecan, epirubicin, or etoposide led to strong synergy in a subset of resistant SCLC cells. Combination treatment with entinostat and cisplatin significantly decreased tumor growth in vivo. Proteomic analysis comparing the groups of SCLC cell lines with synergistic and additive response patterns indicated alterations in cell-cycle regulation and DNA damage repair. Cell-cycle analysis revealed that cells exhibiting synergistic drug responses displayed a shift from G1 to S-phase compared with cells showing additive features upon dual treatment. Comet assays demonstrated more DNA damage and decreased base excision repair in SCLC cells more responsive to combination therapy. Conclusions: In this study, we decipher the molecular processes behind synergistic interactions between chemotherapy and HDAC inhibition. Moreover, we report novel mechanisms to overcome drug resistance in SCLC, which may be relevant to increasing therapeutic success.
Novel Clinical Trial Designs with Dose Optimization to Improve Long-term Outcomes
Authors: Peter F. Thall, Yong Zang, Andrew G. Chapple, Ying Yuan, Ruitao Lin, David Marin, Pavlos Msaouel
Journal: Clinical Cancer Research (2023)

Abstract Conventional designs for choosing a dose for a new therapy may select doses that are unsafe or ineffective and fail to optimize progression-free survival time, overall survival time, or response/remission duration. We explain and illustrate limitations of conventional dose-finding designs and make four recommendations to address these problems. When feasible, a dose-finding design should account for long-term outcomes, include screening rules that drop unsafe or ineffective doses, enroll an adequate sample size, and randomize patients among doses. As illustrations, we review three designs that include one or more of these features. The first illustration is a trial that randomized patients among two cell therapy doses and standard of care in a setting where it was assumed on biological grounds that dose toxicity and dose–response curves did not necessarily increase with cell dose. The second design generalizes phase I–II by first identifying a set of candidate doses, rather than one dose, randomizing additional patients among the candidates, and selecting an optimal dose to maximize progression-free survival over a longer follow-up period. The third design combines a phase I–II trial and a group sequential randomized phase III trial by using survival time data available after the first stage of phase III to reoptimize the dose selected in phase I–II. By incorporating one or more of the recommended features, these designs improve the likelihood that a selected dose or schedule will be optimal, and thus will benefit future patients and obtain regulatory approval.
Short-term effectiveness and safety of rituximab versus cyclophosphamide for life-threatening ANCA-associated vasculitis: a propensity score analysis of the real-world nationwide database
Authors: Yuichi Ishikawa, Kei Tokutsu, Shingo Nakayamada, Aya Kuchiba, Kiyohide Fushimi, Shinya Matsuda, Yoshiya Tanaka
Journal: Annals of the Rheumatic Diseases (2023)

Objectives Life-threatening antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with rapidly progressive glomerulonephritis (RPGN) and/or alveolar haemorrhage (AH) has a poor prognosis. Rituximab (RTX) is as effective as cyclophosphamide (CY) in remission induction therapy; however, the effectiveness and safety of RTX have not been established in life-threatening AAV. This study aimed to investigate the short-term effectiveness and safety of RTX in life-threatening AAV with RPGN and/or AH. Methods Between April 2018 and March 2020, cases treated with systemic glucocorticoids and RTX or intravenous CY (IVCY) was extracted from a Japanese nationwide inpatient database. Effectiveness was evaluated by in-hospital mortality and severe renal dysfunction requiring haemodialysis (HD) at discharge. Safety was evaluated by the in-hospital incidence of infections. The propensity score (PS) for RTX was estimated. Multivariable Cox and logistic regression with adjustment for PS were conducted to estimate the association of RTX with outcomes. Results From 16 001 612 hospitalised records, 687 life-threatening AAV cases were extracted. No significant difference in in-hospital mortality (adjusted HR 1.06; 95% CI 0.62 to 1.80) was found between the groups. Although the RTX group had a lower risk of fungal infections (adjusted OR (aOR) 0.45; 95% CI 0.23 to 0.84) and pneumocystis pneumonia (aOR 0.58; 95% CI 0.32 to 1.00), they might have an increased risk of severe renal dysfunction requiring HD at discharge (aOR 2.58; 95% CI 1.02 to 6.91). Conclusions In life-threatening AAV, RTX has similar short-term effectiveness on mortality to IVCY. Although RTX might have a lower risk of fungal infections and pneumocystis pneumonia, the short-term renal prognosis might be inferior to IVCY.
Optimal measurement of gastric emptying of solids in gastroparesis or functional dyspepsia: evidence to establish standard test
Authors: Michael Camilleri, Ting Zheng, Kia Vosoughi, Camille Lupianez-Merly, Deborah Eckert, Irene Busciglio, Duane Burton, Saam Dilmaghani
Journal: Gut (2023)

Objective Symptoms in gastroparesis (Gp) and functional dyspepsia (FD) overlap; using egg protein substitute to measure gastric emptying of solids (GES), ~40% of patients are reclassified from Gp to FD, and vice versa. Our aim was to assess inter-individual and intra-individual coefficients of variation (COV) in GES in symptomatic patients with Gp or FD with documented slow or normal GES, respectively. Design Scintigraphic GES (T 1/2 and GE% at 2 and 4 hours) using a 320 kcal real egg meal (30% fat) was tested in the following: single measurements in 20 patients with diabetes mellitus (10 each type 1 and type 2); repeat GES to estimate COV intra measured: 3 days apart in 9 Gp, 4 weeks apart in 21 Gp and 18 with FD with normal GE assigned to placebo and in 70 patients at 94.3 weeks (median) apart. Results COV inter for GE% at 4 hours and GE T 1/2 were respectively 14.2% and 23.5% in FD and 27.5% and 33% in Gp; COV intra for GE% at 4 hours and GE T 1/2 up to 4 weeks apart were 23.4% and 37.9% in FD and 20.1% and 33% in Gp. GE% at 2 hours showed less consistent results. However, &gt;85% retained original diagnosis as normal or delayed. From clinical GES to baseline research for Gp group, repeat GES (after treatment) showed the COV intra for GE% at 4 hours was 37.3% at median 94.3 weeks, with 26/70 changed diagnoses. Conclusion The 320 kcal (30% fat) GES scintigraphic test provides consistent diagnosis in &gt;85% and should be the standard test for suspected gastric emptying disorders.
RANK Expression as an Independent Predictor for Response to Neoadjuvant Chemotherapy in Luminal-Like Breast Cancer: A Translational Insight from the GeparX Trial
Authors: Theresa Link, Jens-Uwe Blohmer, Wolfgang D. Schmitt, Jan Dominik Kuhlmann, Marianne Just, Michael Untch, Oliver Stotzer, Peter A. Fasching, Marc Thill, Mattea Reinisch, Andreas Schneeweiss, Pauline Wimberger, Sabine Seiler, Jens Huober, Christian Jackisch, Kerstin Rhiem, Claus Hanusch, Bruno V. Sinn, Valentina Nekljudova, Sibylle Loibl, Carsten Denkert
Journal: Clinical Cancer Research (2023)

Abstract Purpose: The GeparX study investigated whether denosumab as add-on treatment to nab-paclitaxel–based neoadjuvant chemotherapy (NACT) with two different schedules (125 mg/m² weekly vs. day 1, 8 every 22 days) may increase pathologic complete response (pCR) rate. The addition of denosumab to NACT did not improve pCR rates as recently published. In this study, we investigated whether receptor activator of nuclear factor-kappa B (RANK) expression, as part of the denosumab target pathway: (i) may retrospectively identify a subgroup of patients with additional clinical benefit of denosumab or (ii) may predict response to nab-paclitaxel NACT. Experimental Design: RANK protein was IHC-stained on pre-therapeutic core biopsies from patients of the GeparX study (n = 667) with the antibody RANK/Envision System HRP (DAB) and was analyzed for the percentage of membranous RANK tumor cell staining (&amp;gt;5% RANKhigh vs. ≤5% RANKlow). Results: We could not identify any patient subgroup with differential response under denosumab add-on treatment in patients with RANKhigh expression [139/667, 20.8%; OR, 0.86; 95% confidence interval (CI), 0.44–1.68; P = 0.667] or RANKlow expression (528/667 (79.2%) OR, 1.10; 95% CI, 0.78–1.56; P = 0.589; Pinteraction = 0.528). However, the pCR rate was higher in the RANKhigh subgroup compared with RANKlow (50% vs. 39%; OR, 1.52; 95% CI, 1.04–2.21; P = 0.037). RANK expression constituted an independent predictor of response to NACT frequently in patients with luminal-like subtype (HR+/HER2−; OR, 2.98; 95% CI, 1.30–6.79; P = 0.010). No predictive value of RANK expression among the different nab-paclitaxel regimens was observed. Conclusion: We report RANK expression to be an independent predictive biomarker for response to NACT in patients with luminal-like breast cancer.
Poor oral health influences head and neck cancer patient survival: an International Head and Neck Cancer Epidemiology Consortium pooled analysis
Authors: Jason Tasoulas, Douglas R Farquhar, Siddharth Sheth, Trevor Hackman, Wendell G Yarbrough, Chris B Agala, Alzina Koric, Luca Giraldi, Eleonora Fabianova, Jolanta Lissowska, Beata Świątkowska, Marta Vilensky, Victor Wünsch-Filho, Marcos Brasilino de Carvalho, Rossana Verónica Mendoza López, Ivana Holcátová, Diego Serraino, Jerry Polesel, Cristina Canova, Lorenzo Richiardi, Jose P Zevallos, Andy Ness, Miranda Pring, Steve J Thomas, Tom Dudding, Yuan-Chin Amy Lee, Mia Hashibe, Paolo Boffetta, Andrew F Olshan, Kimon Divaris, Antonio L Amelio
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Poor oral health has been identified as a prognostic factor potentially affecting the survival of patients with head and neck squamous cell carcinoma. However, evidence to date supporting this association has emanated from studies based on single cohorts with small-to-modest sample sizes. Methods Pooled analysis of 2449 head and neck squamous cell carcinoma participants from 4 studies of the International Head and Neck Cancer Epidemiology Consortium included data on periodontal disease, tooth brushing frequency, mouthwash use, numbers of natural teeth, and dental visits over the 10 years prior to diagnosis. Multivariable generalized linear regression models were used and adjusted for age, sex, race, geographic region, tumor site, tumor-node-metastasis stage, treatment modality, education, and smoking to estimate risk ratios (RR) of associations between measures of oral health and overall survival. Results Remaining natural teeth (10-19 teeth: RR = 0.81, 95% confidence interval [CI] = 0.69 to 0.95; ≥20 teeth: RR = 0.88, 95% CI = 0.78 to 0.99) and frequent dental visits (&amp;gt;5 visits: RR = 0.77, 95% CI = 0.66 to 0.91) were associated with better overall survival. The inverse association with natural teeth was most pronounced among patients with hypopharyngeal and/or laryngeal, and not otherwise specified head and neck squamous cell carcinoma. The association with dental visits was most pronounced among patients with oropharyngeal head and neck squamous cell carcinoma. Patient-reported gingival bleeding, tooth brushing, and report of ever use of mouthwash were not associated with overall survival. Conclusions Good oral health as defined by maintenance of the natural dentition and frequent dental visits appears to be associated with improved overall survival among head and neck squamous cell carcinoma patients.